Adipocyte mesenchymal transition contributes to mammary tumor progression

Zhu, Qianzheng; Zhu, Yi; Hepler, Chelsea; Zhang, Qianbin; Park, Jiyoung; Gliniak, Christy; Henry, Gervaise H.; Crewe, Clair; Bu, Dawei; Zhang, Zhuzhen; Zhao, Shangang; Morley, Thomas S.; Li, Na; Kim, Dae-Seok; Strand, Douglas W.; Deng, Yingfeng; Robino, Jacob J; Varlamov, Oleg; Gordillo, Ruth; Kolonin, Mikhail G.; Kusminski, Christine M.; Gupta, Rana K.; Scherer, Philipp E.

doi:10.1016/j.celrep.2022.111362

Cited by 53 publications

(47 citation statements)

References 40 publications

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“…Our data show that the net effect of activated Wnt signaling is reduced accumulation of TGs and increased FFAs. Interestingly, it was recently reported that mammary tumor cells stimulated their adjacent adipocytes to convert TGs into FAs (Zhu et al, 2022). FAs can be absorbed by cancer cells for the biogenesis of phospholipids, the major membrane materials required for proliferation of cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Wingless signaling promotes lipid mobilization through signal-induced transcriptional repression

Liu

Hemba-Waduge

et al. 2023

Preprint

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Conserved Wnt/Wingless signaling plays pivotal roles in regulating normal development and energy metabolism in metazoans, and aberrant activation of Wnt signaling drives the pathogenesis of many diseases including cancer. However, the role of Wnt signaling in regulating cellular lipid homeostasis, particularly lipid mobilization, remains poorly understood. Here we show that canonical Wg signaling inhibits lipid accumulation in Drosophila larval adipocytes by stimulating lipid catabolism while simultaneously inhibiting lipogenesis. Using a combination of RNA-sequencing and CUT&RUN assays, we identified a battery of Wg target genes encoding key factors required for lipogenesis (such as FASN1 and AcCoS), lipolysis (such as lipid droplet-associated proteins Lsd-1 and Lsd-2), and fatty acid β-oxidation in the mitochondria and peroxisome (e.g., CPT1 and CRAT), most of which are directly repressed by active Wg signaling. Furthermore, lipid accumulation defects caused by active Wg signaling are rescued by either ectopically expressing Lsd-1 and Lsd-2 or depleting the transcriptional repressor Aef1, whose binding motif was identified in 52% of Wg signaling-repressed genes. These findings suggest that active Wg signaling reduces intracellular lipid accumulation by inhibiting lipogenesis and fatty acid β-oxidation and by promoting lipolysis and lipid mobilization, and Wg signaling-induced transcriptional repression play a prominent role in these converging mechanisms.

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Section: Discussionmentioning

confidence: 99%

Wingless signaling promotes lipid mobilization through signal-induced transcriptional repression

Liu

Hemba-Waduge

et al. 2023

Preprint

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“…Notably, recent evidence suggested that CAAs at the invasive front of the tumor mass undergo the AMT process consisting of the phenotypic switch of adipocytes toward myofibroblast/CAF-like cells endowed with all the pro-tumoral features typical of CAFs [ 31 , 47 ]. Thereby, the AMT, by fueling the CAF compartment, becomes a pro-tumoral process itself.…”

Section: Discussionmentioning

confidence: 99%

“…Notably, very recent findings underline the importance of AMT, a process by which pre-adipocytes/adipocytes transdifferentiate into pathogenic myofibroblast-like cells, observed in systemic sclerosis and other fibrotic diseases, where it was deemed as relevant in the formation of the pro-fibrotic myofibroblasts responsible for excessive extracellular matrix synthesis/deposition and remodeling [ 21 , 22 , 23 , 24 ]. Adipocytes and, more precisely, cancer-associated adipocytes (CAAs) are then being extensively investigated, and evidence supports their active contribution to cancer progression, especially in mammary tumors [ 20 , 25 , 26 , 27 , 28 , 29 ], where they represent 90% of the breast tissue [ 30 ] and were found to give rise to the generation of cancer-associated fibroblast (CAF)-like cells with pro-tumoral activity [ 31 ]. To date, it has never been explored whether extracellular lactic acidosis might favor AMT.…”

Section: Introductionmentioning

confidence: 99%

Extracellular Lactic Acidosis of the Tumor Microenvironment Drives Adipocyte-to-Myofibroblast Transition Fueling the Generation of Cancer-Associated Fibroblasts

Andreucci

Fioretto

Rosa

et al. 2023

Cells

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Lactic acidosis characterizes the tumor microenvironment (TME) and is involved in the mechanisms leading to cancer progression and dissemination through the reprogramming of tumor and local host cells (e.g., endothelial cells, fibroblasts, and immune cells). Adipose tissue also represents a crucial component of the TME which is receiving increasing attention due to its pro-tumoral activity, however, to date, it is not known whether it could be affected by the acidic TME. Now, emerging evidence from chronic inflammatory and fibrotic diseases underlines that adipocytes may give rise to pathogenic myofibroblast-like cells through the adipocyte-to-myofibroblast transition (AMT). Thus, our study aimed to investigate whether extracellular acidosis could affect the AMT process, sustaining the acquisition by adipocytes of a cancer-associated fibroblast (CAF)-like phenotype with a pro-tumoral activity. To this purpose, human subcutaneous adipose-derived stem cells committed to adipocytes (acADSCs) were cultured under basal (pH 7.4) or lactic acidic (pH 6.7, 10 mM lactate) conditions, and AMT was evaluated with quantitative PCR, immunoblotting, and immunofluorescence analyses. We observed that lactic acidosis significantly impaired the expression of adipocytic markers while inducing myofibroblastic, pro-fibrotic, and pro-inflammatory phenotypes in acADSCs, which are characteristic of AMT reprogramming. Interestingly, the conditioned medium of lactic acidosis-exposed acADSC cultures was able to induce myofibroblastic activation in normal fibroblasts and sustain the proliferation, migration, invasion, and therapy resistance of breast cancer cells in vitro. This study reveals a previously unrecognized relationship between lactic acidosis and the generation of a new CAF-like cell subpopulation from adipocytic precursor cells sustaining tumor malignancy.

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“…One report showed that obesity-dependent ECM deposition in liver tissue contributed to hepatocarcinoma development [ 80 ]. However, most previous studies have focused on the role of ECM remodeling in adipose tissue in obesity-associated cancer progression [ 15 , 40 , 81 , 82 ].…”

Section: Obesity-associated Fibrosis and Ecm Remodeling In Cancer Pro...mentioning

confidence: 99%

Obesity-Associated ECM Remodeling in Cancer Progression

2022

Cancers

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Adipose tissue, an energy storage and endocrine organ, is emerging as an essential player for ECM remodeling. Fibrosis is one of the hallmarks of obese adipose tissue, featuring excessive ECM deposition and enhanced collagen alignment. A variety of ECM components and ECM-related enzymes are produced by adipocytes and myofibroblasts in obese adipose tissue. Data from lineage-tracing models and a single-cell analysis indicate that adipocytes can transform or de-differentiate into myofibroblast/fibroblast-like cells. This de-differentiation process has been observed under normal tissue development and pathological conditions such as cutaneous fibrosis, wound healing, and cancer development. Accumulated evidence has demonstrated that adipocyte de-differentiation and myofibroblasts/fibroblasts play crucial roles in obesity-associated ECM remodeling and cancer progression. In this review, we summarize the recent progress in obesity-related ECM remodeling, the mechanism underlying adipocyte de-differentiation, and the function of obesity-associated ECM remodeling in cancer progression.

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Adipocyte mesenchymal transition contributes to mammary tumor progression

Cited by 53 publications

References 40 publications

Wingless signaling promotes lipid mobilization through signal-induced transcriptional repression

Wingless signaling promotes lipid mobilization through signal-induced transcriptional repression

Extracellular Lactic Acidosis of the Tumor Microenvironment Drives Adipocyte-to-Myofibroblast Transition Fueling the Generation of Cancer-Associated Fibroblasts

Obesity-Associated ECM Remodeling in Cancer Progression

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